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Synthesis and SAR Studies of Antibacterial Peptidyl Derivatives Based upon the Binding Site of Human Cystatin C

Dzierżyńska, Maria ; Sikorska, Emilia ; Pogorzelska, Aneta ; Mulkiewicz, Ewa ; Sawicka, Justyna ; Wyrzykowski, Dariusz ; Małuch, Izabela ; Grubb, Anders LU ; Kasprzykowski, Franciszek and Rodziewicz-Motowidło, Sylwia (2019) In Protein and Peptide Letters 26(6). p.423-434
Abstract

BACKGROUND: Antibacterial peptidyl derivative - Cystapep 1, was previously found to be active both against antibiotic-resistant staphylococci and streptococci as well as antibiotic-susceptible strains of these species. Therefore, it is a promising lead compound to search for new antimicrobial peptidomimetics.

OBJECTIVES: We focused on identifying structural elements that are responsible for the biological activity of Cystapep 1 and its five analogues. We tried to find an answer to the question about the mechanism of action of the tested compounds. Therefore we have investigated in details the possibility of interacting these compounds with biological membrane mimetics.

METHODS: The subject compounds were synthesized in... (More)

BACKGROUND: Antibacterial peptidyl derivative - Cystapep 1, was previously found to be active both against antibiotic-resistant staphylococci and streptococci as well as antibiotic-susceptible strains of these species. Therefore, it is a promising lead compound to search for new antimicrobial peptidomimetics.

OBJECTIVES: We focused on identifying structural elements that are responsible for the biological activity of Cystapep 1 and its five analogues. We tried to find an answer to the question about the mechanism of action of the tested compounds. Therefore we have investigated in details the possibility of interacting these compounds with biological membrane mimetics.

METHODS: The subject compounds were synthesized in solution, purified and characterized by HPLC and mass spectrometry. Then, the staphylococci susceptibility tests were performed and their cytotoxicity was established. The results of Cystapep 1 and its analogues interactions with model target were examined using the DSC and ITC techniques. At the end the spatial structures of the tested peptidomimetics using NMR technique were obtained.

RESULTS: Antimicrobial and cytotoxicity tests show that Cystapep 1 and its peptidomimetic V are good drug candidates. DSC and ITC studies indicate that disruption of membrane is not the only possible mechanism of action of Cystapep 1-like compounds. For Cystapep 1 itself, a multi-step mechanism of interaction with a negatively charged membrane is observed, which indicates other processes occurring alongside the binding process. The conformational analysis indicated the presence of a hydrophobic cluster, composed of certain side chains, only in the structures of active peptidomimetics. This can facilitate the anchoring of the peptidyl derivatives to the bacterial membrane.

CONCLUSION: An increase in hydrophobicity of the peptidomimetics improved the antimicrobial activity against S. aureus, however there is no simple correlation between the biological activity and the strength of interactions of the peptidyl with bacterial membrane.

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author
publishing date
type
Contribution to journal
publication status
published
subject
in
Protein and Peptide Letters
volume
26
issue
6
pages
12 pages
publisher
Bentham Science Publishers
external identifiers
  • scopus:85070631799
  • pmid:30864495
ISSN
0929-8665
DOI
10.2174/0929866526666190311162716
language
English
LU publication?
no
id
83caa8db-07e7-4e6b-877b-5576a33753d7
date added to LUP
2019-05-21 13:04:21
date last changed
2019-09-17 04:54:21
@article{83caa8db-07e7-4e6b-877b-5576a33753d7,
  abstract     = {<p>BACKGROUND: Antibacterial peptidyl derivative - Cystapep 1, was previously found to be active both against antibiotic-resistant staphylococci and streptococci as well as antibiotic-susceptible strains of these species. Therefore, it is a promising lead compound to search for new antimicrobial peptidomimetics.</p><p>OBJECTIVES: We focused on identifying structural elements that are responsible for the biological activity of Cystapep 1 and its five analogues. We tried to find an answer to the question about the mechanism of action of the tested compounds. Therefore we have investigated in details the possibility of interacting these compounds with biological membrane mimetics.</p><p>METHODS: The subject compounds were synthesized in solution, purified and characterized by HPLC and mass spectrometry. Then, the staphylococci susceptibility tests were performed and their cytotoxicity was established. The results of Cystapep 1 and its analogues interactions with model target were examined using the DSC and ITC techniques. At the end the spatial structures of the tested peptidomimetics using NMR technique were obtained.</p><p>RESULTS: Antimicrobial and cytotoxicity tests show that Cystapep 1 and its peptidomimetic V are good drug candidates. DSC and ITC studies indicate that disruption of membrane is not the only possible mechanism of action of Cystapep 1-like compounds. For Cystapep 1 itself, a multi-step mechanism of interaction with a negatively charged membrane is observed, which indicates other processes occurring alongside the binding process. The conformational analysis indicated the presence of a hydrophobic cluster, composed of certain side chains, only in the structures of active peptidomimetics. This can facilitate the anchoring of the peptidyl derivatives to the bacterial membrane.</p><p>CONCLUSION: An increase in hydrophobicity of the peptidomimetics improved the antimicrobial activity against S. aureus, however there is no simple correlation between the biological activity and the strength of interactions of the peptidyl with bacterial membrane.</p>},
  author       = {Dzierżyńska, Maria and Sikorska, Emilia and Pogorzelska, Aneta and Mulkiewicz, Ewa and Sawicka, Justyna and Wyrzykowski, Dariusz and Małuch, Izabela and Grubb, Anders and Kasprzykowski, Franciszek and Rodziewicz-Motowidło, Sylwia},
  issn         = {0929-8665},
  language     = {eng},
  month        = {07},
  number       = {6},
  pages        = {423--434},
  publisher    = {Bentham Science Publishers},
  series       = {Protein and Peptide Letters},
  title        = {Synthesis and SAR Studies of Antibacterial Peptidyl Derivatives Based upon the Binding Site of Human Cystatin C},
  url          = {http://dx.doi.org/10.2174/0929866526666190311162716},
  doi          = {10.2174/0929866526666190311162716},
  volume       = {26},
  year         = {2019},
}